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Any disorder caused by a heterozygous variant or biallelic variants in the AFG3L2 gene and characterized by a spectrum of phenotypes including optic atrophy and/or spastic ataxia.
Clinical Presentation
Built from Human Phenotype Ontology (HPO) phenotype annotations and GeneReviews clinical descriptions. Features represent findings documented across known cases — not an exhaustive list of possible symptoms.
No HPO annotations are available for this condition.
GeneReviews
Clinical Guidance
To date, hundreds of individuals have been identified with an AFG3L2-related neurologic disorder [, , , , , , , ]. The following description of the phenotypic features associated with these conditions is based on these reports and highlights the four distinct clinical presentations associated with AFG3L2-related neurologic disorders.
Spinocerebellar Ataxia Type 28 (SCA28)
Diagnosis
Drawn from GeneReviews diagnostic guidelines, newborn screening panel status (RUSP), and ClinGen gene-disease validity classifications. Reflects current clinical evidence and consensus where available.
GeneReviews
Diagnostic Criteria
No consensus clinical diagnostic criteria for AFG3L2-related neurologic disorders have been published.
Suggestive Findings
The diagnosis of an AFG3L2-related neurologic disorder should be considered in probands with the following clinical and imaging findings and family history.
Compiled from FDA-approved drug records, orphan drug designations, and FDA Adverse Event Reporting System (FAERS) safety data. GeneReviews management guidance is included where available.
No approved treatments are currently available for AFG3L2-related optic atrophy and/or spastic ataxia spectrum. The disease remains an area of unmet medical need.
GeneReviews
Management Guidelines
No clinical practice guidelines for AFG3L2-related neurologic disorders have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an AFG3L2-related neurologic disorder, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Prognosis
Based on GeneReviews surveillance recommendations, HPO phenotype frequency and severity annotations, and published prevalence estimates from Orphanet and OMIM.
GeneReviews
Surveillance Guidelines
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in are recommended.
| • Neurologic assessment for progression of ataxia, UMN or LMN signs, dystonia parkinsonism, autonomic dysfunction
Research Landscape
Sourced from ClinicalTrials.gov and PubMed. Publication types are classified using NLM-curated article metadata; research type breakdowns reflect the nature of published work for this disease.
No clinical trials have been registered for AFG3L2-related optic atrophy and/or spastic ataxia spectrum.
29 publications have been identified in PubMed for AFG3L2-related optic atrophy and/or spastic ataxia spectrum. Research spans Case Report / Case Series (31%), Basic Science / Preclinical (31%), and Epidemiology / Natural History (21%).
Research Type
Count
% of Total
Patient case studies
9
31%
Data assembled from 3 of 12 sources · Last updated Sep 20, 2026, 5:40 PM UTC
Diseases are connected by shared genes, phenotypes, therapeutic targets, and MONDO disease hierarchy. The Rare badge reflects Kisho's rarity classification — scored from authoritative sources including OMIM, Orphanet, orphan drug designations, clinical trial activity, and published prevalence data.
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FAQ
Frequently Asked Questions
Common questions about AFG3L2-related optic atrophy and/or spastic ataxia spectrum
AFG3L2-related optic atrophy and/or spastic ataxia spectrum is a condition caused by changes in the AFG3L2 gene. It is defined by the presence of optic atrophy, which affects the nerves in the eyes, and spastic ataxia, which involves problems with movement and coordination.
The condition can result from a single variant (heterozygous) or changes in both copies (biallelic) of the AFG3L2 gene. These genetic alterations lead to a range of features, and the extent of symptoms can vary from person to person.
People with this condition may experience vision loss or disturbances due to optic atrophy. They might also have issues with muscle control, including stiffness or problems with balance and coordination, which are related to spastic ataxia.
This condition is caused by variants in the AFG3L2 gene. Changes in one copy (heterozygous) or both copies (biallelic) of the gene can disrupt normal cell function, leading to the symptoms seen in the condition. Associated genes include AFG3L2.
Age of onset and progression. The usual age at onset is early adulthood (26.5 ± 17.2 years); the range is from birth to 74 years, although infantile presentation is rare. The disease course is slowly progressive with or without slight impairment of functional autonomy even decades after onset. Most individuals remain ambulatory throughout life. Presentation.
Spinocerebellar ataxia type 28 (SCA28). The ataxic gait of individuals with SCA28 is indistinguishable from that seen in other adult-onset inherited or acquired ataxias. When the family history suggests autosomal dominant inheritance, all other autosomal dominant cerebellar ataxias should be considered (see Hereditary Ataxia Overview). Spastic ataxia type 5 (SPAX5). The differential diagnosis of SPAX5 should include other spastic ataxias and complex ataxias. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR) presents with a clinical phenotype that closely resembles SCA28; therefore, the differential diagnosis is similar to that of SCA28. Optic atrophy type 12 (OPA12). Optic atrophy observed in individuals with OPA12 is clinically indistinguishable from that seen in other forms of optic atrophy. See for selected genes of interest in the differential diagnosis of AFG3L2-related neurologic disorders. Table 2. Genes of Interest in the Differential Diagnosis of AFG3L2-Related Neurologic Disorders
Polyglutamine expansions; Typically present before age 40 years; More rapidly progressive than SCA28 AFG3L2-SCAR; Assoc w/brain stem involvement on MRI AD
FGF14
GAA-FGF14-related ataxia (SCA27B)
Adult-onset ataxia; Typically begins w/episodic ataxia assoc w/downbeat nystagmus AR
—
—
APTX
Ataxia w/oculomotor apraxia type 1 (AOA1) (OMIM 208920)
AOA1 AOA2 are childhood-onset disorders characterized by marked peripheral involvement, incl severe polyneuropathy.; They are typically more rapidly progressive than SCA28 AFG3L2-SCAR. AR
SETX
Ataxia w/oculomotor apraxia type 2 (AOA2) AR
Chronic cough can precede neurologic symptoms by several decades. Spastic ataxia (SPAX)(OMIM PS108600)
AR
—
—
—
CHP1
SPAX9
Spastic ataxia that may present w/childhood onset AR
Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties. Carbamazepine and phenytoin may exacerbate myoclonus in spastic ataxia type 5 (SPAX5).
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
| Annually or more often for an acute exacerbation
Physiatry OT/PT assessment of mobility self-help skills as they relate to ataxia, spasticity, weakness | Annually or more often for an acute exacerbation
EEG seizure history (in SPAX5) | Every 6 mos or annually; more often for an acute exacerbation
Dysarthria
| Assess need for alternative communication method or speech therapy. | Per disease progression
Dysphagia
| Assess aspiration risk feeding methods.
Weight/ Nutritional status
| • Monitor BMI.
Consult nutritionist.
High-calorie supplementation
| Annually
Ophthalmologic
involvement | • Assessment of nystagmus, ophthalmoparesis, ptosis.
Assessment of visual acuity photophobia.
Cognitive/
neurobehavioral/
psychiatric manifestations | Evaluate mood, signs of psychosis, cognitive complaints, cognitive deterioration (e.g., using CCAS scale) to identify need for pharmacologic psychotherapeutic interventions. | Per disease progression development of psychiatric manifestations
Family/Community
| Assess family need for social work support (e.g., pall...
Borel F (2026). [PMID: 41483232](https://pubmed.ncbi.nlm.nih.gov/41483232/). *Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology*. [Case Report / Case Series]
Rudaks LI (2025). [PMID: 40007153](https://pubmed.ncbi.nlm.nih.gov/40007153/). *Annals of clinical and translational neurology*. [Diagnostic / Biomarker]
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